Non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) are a central component of anti-HIV therapy (Prajapati et al., 2009, Bioorg. Med. Chem. 17:5744; de Bethune, 2010, Antiviral Res. 85:75). There are five FDA-approved NNRTI drugs: nevirapine, delavirdine, efavirenz, etravirine, and rilpivirine. In view of the rapid mutation of the virus, NNRTIs are given in combination therapies. Though the NNRTI class has demonstrated utility in treating HIV, further improvements are necessary to address issues of safety, administration and virologic failure (Chiao et al., 2009, Curr. Opin. Drug Disc. Dev. 12:53; Adams et al., 2010, Ann. Pharmacotherapy 44:157; Molina et al., 2011, Lancet 378:238). There is also need to respond to the emergence of pan-resistant viral variants and unknown effects of long-term treatment (Richman et al., 2009, Science 323:1304).
Among the five FDA-approved NNRTI drugs, the most recent drugs are etravirine and rilpivirine. These diarylpyrimidines are very active in cell assays against variant forms of HIV-1 that incorporate mutations in the vicinity of the NNRTI binding site (Gillemont et al., 2005, J. Med. Chem. 48:2072; Janssen et al., 2005, J. Med. Chem. 48:1901). The earliest approved NNRTIs (nevirapine and delavirdine) have poor activity against most common mutations. Though the second-generation compound efavirenz performs well against variants bearing the clinically prevalent Tyr181 Cys mutation, resistance arises from other common variants such as those including Lys103Asn (de Bethune, 2010, Antiviral Res. 85:75; Gillemont et al., 2005, J. Med. Chem. 48:2072; Janssen et al., 2005, J. Med. Chem. 48:1901). The clinical significance of efavirenz and rilpivirine is particularly great since they are incorporated into the once-a-day combination therapies Atripla and Complera, respectively (Permpalung et al., 2012, Expert Opin. Pharmacotherapy 13:2301). The other two active components of these pills are the same—the nucleosides emtricitabine and tenofovir. Though the performance in cell-based assays is far better for rilpivirine than for efavirenz, surprisingly more virologic failure is observed for patients under treatment with Complera than Atripla (Permpalung et al., 2012, Expert Opin. Pharmacotherapy 13:2301; Molina et al., 2011, Lancet 378:238; Lyseng-Willamson and Scott, 2012, Clin. Drug Investig. 32:715). These results highlight the need for improvements in the NNRTI class, including novel agents that allow for lower dosages and side effects. In particular, aminoazine NNRTIs have poor solubility, which often leads to low bioavailability, difficulties in formulation, and accumulation in fatty tissues (Lipinski et al., 2001, Adv. Drug Deliv. Rev. 46:3; Jorgensen and Duffy, 2002, Adv. Drug Deliv. Rev. 54:355).
Most oral drugs have aqueous solubility (S) in the range 10−5 to 10−2 M, which for a drug with a molecular weight of 400 corresponds to 4 to 4,000 μg/mL. Rarely does an FDA-approved oral drug have S near neutral pH below 10−6 M (Jorgensen and Duffy, 2002, Adv. Drug Deliv. Rev. 54:355). However, rilpivirine is practically insoluble in water (20 ng/mL at pH 7.0) (Janssen et al., 2005, J. Med. Chem. 48:1901), which translates to S of 5×10−8 M. This drug appears to have an unusual absorption mechanism involving aggregates (Frenkel et al., 2005, J. Med. Chem. 48:1974). For etravirine, the solubility is also much lower than 1 μg/mL, and extensive formulation work was needed to bring the daily dosage to 0.4 g per day (Weuts et al., 2011, J. Pharm. Sci. 100:260).
In view of its low solubility, dapivirine is being evaluated as a vaginal microbicide (Saxena et al., 2009, AIDS 23:917). This was also the fate of UC-781, an early NNRTI with poor solubility (<30 ng/mL) (Yang et al., 2008, AAPS J. 10:606). Interestingly, the daily dosage for nevirapine, like etravirine, is 0.4 g despite the fact that its potency towards wild-type HIV-1 is ca. 100-fold less than for etravirine. An important factor is undoubtedly that the observed aqueous solubility of nevirapine is 167 μg/mL (Morelock et al., 1994, J. Pharm. Sci. 83:948). This observation demonstrates that it is possible to have a viable NNRTI that has an EC50 of ca. 100 nM in cell assays, if the compound has good solubility and bioavailability.
There is a need in the art for non-nucleoside compounds with improved solubility that inhibit HIV-1 reverse transcriptase. These compounds should be useful for the treatment of HIV-1 infection. The present invention addresses this unmet need.